Pathogenicity of the emerging pathogen Kingella kingae

新出现的病原体金氏菌的致病性

• 批准号: 10559927
• 负责人: Joseph W. St. Geme
• 金额: $ 44.5万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-04 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559927
• 关键词: 4 year old; Accounting; Acute suppurative arthritis due to bacteria; Address; Adult; Alleles; Anabolism; Animals; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Therapy; Antimicrobial Resistance; Articulation; Awareness; Bacterial Adhesins; Biological Assay; Biology; Blood Circulation; Bone Growth; Child; Chronic; Culture Techniques; Detection; Development; Diagnostic Procedure; Diphtheria Toxin; Disease; Distant; Endocardium; Family; Functional disorder; Future; Glycoconjugates; Human; Immune response; Incidence; Infant; Infection; Invaded; Joint Dislocation; Joints; Kingella kingae; Lipopolysaccharides; Mediating; Modeling; Monobactams; Morbidity - disease rate; Nature; Neisseria gonorrhoeae; Neisseriaceae; Organism; Oropharyngeal; Osteomyelitis; Pathogenesis; Pathogenicity; Phagocytosis; Pilum; Polysaccharides; Production; Property; Rattus; Reporting; Residual state; Resistance; Sampling; Sepsis; Series; Serum; Side; Site; Structure; Surface; Testing; Toxin; Vaccine Antigen; Vaccines; Virulence; Virulence Factors; Work; antimicrobial peptide; bacterial resistance; beta-Lactam Resistance; beta-Lactamase; bone; capsule; disorder prevention; emerging pathogen; gene product; immunogenic; immunogenicity; improved; insight; joint infection; joint mobilization; member; molecular diagnostics; mortality; multiorgan injury; mutant; neutrophil; pathogen; pathogenic bacteria; prevent; protective efficacy; skeletal

Kingella kingae is an invasive gram-negative pathogen that has been recognized recently as a leading cause of bone and joint infections in young children, accounting for up to 88% of osteoarticular cases in children <4 years old. In addition, K. kingae is an important cause of invasive bloodstream infections in young children. Complications of osteoarticular infections in children include abnormalities in bone growth, limitation of joint mobility, unstable joint articulation, and chronic joint dislocation, resulting in residual skeletal dysfunction in 10- 25% of cases. Complications of invasive bloodstream infections include multi-organ injury and mortality. Approximately 25% of K. kingae isolates possess β-lactamase activity, and many of these isolates are resistant to other antibiotics as well, raising concern about approaches to treatment in the future. At present there are no effective strategies to prevent K. kingae disease and the associated morbidity. The pathogenesis of K. kingae disease begins with colonization of the oropharynx, followed by invasion of the bloodstream and spread to bones, joints, and other sites. We have established that isolates of K. kingae produce an exopolysaccharide that is encoded by the pamABCDE locus, is a homopolymer of galactofuranose, is secreted from the organism, and is a critical virulence factor essential for full virulence. We have found that there are 2 distinct exopolysaccharide structures, distinguished by the linkage of the galactofuranose repeating subunit and referred to as type 1 and type 2. Importantly, the exopolysaccharide promotes resistance to serum- mediated killing and neutrophil phagocytosis and thereby promotes K. kingae survival in the bloodstream, indicating that at least some of the exopolysaccharide is anchored to the bacterial surface. Preliminary results indicate that pooled serum from healthy adults and convalescent serum samples from children with invasive K. kingae disease contain antibodies against the exopolysaccharide. In this proposal, we will elucidate the mechanism by which the type 1 and type 2 exopolysaccharides are synthesized and anchored to the bacterial surface. In addition, we will elucidate the pathogenic properties of the type 1 and type 2 exopolysaccharides. We will also elucidate the immunogenicity and protective efficacy of the exopolysaccharides. The proposed studies will provide fundamental insight into K. kingae pathogenicity and basic aspects of bacterial exopolysaccharides. These studies will also facilitate development of a K. kingae vaccine and antibody-based therapeutics against other pathogens with galactofuranose-containing surface structures.

Kingella Kingae是一种侵入性的革兰氏阴性病原体，最近被认为是主要原因 幼儿的骨骼和关节感染，占儿童骨术病例的88％<4 年龄。此外，K. k. k.是幼儿侵入性血液感染的重要原因。 儿童骨关节感染的并发症包括骨骼生长异常，关节的局限性 迁移率，不稳定的关节发音和慢性关节脱位，导致10-的残留骨骼功能障碍 25％的病例。浸润性血液感染的并发症包括多器官损伤和死亡率。 大约25％的K. kingae分离株具有β-内酰胺酶活性，其中许多分离株是 对其他抗生素的抗药性也引起了人们对将来治疗方法的关注。现在 没有有效的策略来预防K. Kingae疾病和相关的发病率。发病机理 K. k. k. ae疾病始于口咽的定殖，然后入侵血液和 扩散到骨头，关节和其他部位。我们已经确定K. k. k. ae的分离物产生了 由pamabcde基因座编码的外多糖是半乳纤维瘤的均聚物，是分泌的 来自生物体，是全病毒至关重要的关键病毒因素。我们发现有2个 独特的外多糖结构，以甲乳素糖重复亚基的连锁 并被称为1型和类型2。重要的是，外多糖促进了对血清的抗性 介导的杀伤和中性粒细胞增多症，从而促进了K. k. k. k. k. k. aae的生存， 表明至少某些外多糖固定在细菌表面上。初步结果 表明来自健康成年人的血清和来自侵入性K的儿童的康复血清样品。 Kingae疾病含有抗外多糖的抗体。在此提案中，我们将阐明 1型和2型外多糖合成并锚定在细菌上的机制 表面。另外，我们将阐明1型和2型外多糖的致病性质。 我们还将阐明外多糖的免疫原性和保护效率。提议 研究将为K. k. k. k. k. k. ae的致病性和细菌的基本方面提供基本见解 外多糖。这些研究还将促进K. Kingae疫苗和基于抗体的开发 针对其他病原体的治疗剂，具有含乙乳素酶的表面结构。